DK149106B - METHOD OF ANALOGUE FOR THE PREPARATION OF 1,2,4-OXADIAZINE DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OR QUATERNARY SALTS THEREOF AND 1,2,4-OXADIAZOLINE-5-OER USED FOR USE - Google Patents

Description

o in 149106

The present invention relates to an analogous process for the preparation of novel 1,2,4-oxadiazine derivatives. or pharmaceutically acceptable acid addition salts or quaternary salts thereof. More specifically, according to the invention, novel 1,2,4-oxadiazine derivatives of the general formula (X) are prepared.

H

/ V 4

R1 - (CH) m - (CH2) n - c / CH2 H

I2 in CH - CH, -N (I) 15

IT

Wherein R10 is independently phenyl which is optionally substituted 1 or 2 times by alkyl of 1-4 carbon atoms or by halogen, R4 means hydrogen or alkyl of 1-4 carbon atoms, R4 is cycloalkyl of 5- 7 carbon atoms or alkyl of 1-6 carbon atoms, or R4 and r5 together represent a group of the general formula (V) 25, CH2) δπί 30 wherein g R is hydrogen or alkoxy of 1-4 carbon atoms and m and n are for 0 or 1, or pharmaceutically acceptable acid addition salts or quaternary salts thereof.

Throughout the description, the following 35 additional symbols will be used: Z is halogen or sulfonyloxy, Y is halogen and Q represents a 3-chloro-2-hydroxypropyl or 2,3-epoxypropyl group.

The term "alkyl" is used to denote straight-chain or branched hydrocarbon groups.

The analogous process of the present invention for the preparation of compounds of general formula (I) is characterized by reacting a compound of general formula (II)

H

R 1 - (CH) - (CH 2) - C 12 CH 2 I m z n & (II)

R2 KL CH - CH2 - Z

Wherein R ·, R₂, m, n and Z are as defined above, with a compound of the general formula (III) R 25 25 /

Hr (III)

V

Wherein R4 and R4 are as defined above, or b) reacting a compound of general formula (IV) S4

35 1 I

R - (CH) - (CH,) - C - N - CH, - CH - CH, -N (IV) l2 2 "II I 2 I 2 Ls R = oy R5 3 o 149106 wherein Ί 2 λ c R, R, R, R, m, n and I are as defined above with a base, and optionally convert an obtained compound of formula (I) into a pharmaceutically acceptable acid addition salt or quaternary salt thereof.

Compounds of general formula (I) are potent

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peripheral vasodilators and hypotensive agents. They increase coronary blood flow, and in addition to their low anti-inflammatory and diuretic activity, they also have strong antiarrhythmic activity.

Closely related oxadiazine derivatives containing a nitrofuryl or a 5-imino substituent are described in C.A., respectively. 75, 20450 (1971), and J. Heterocycl. Chem. 9, 435 (1972). These compounds are stated to have antibacterial activity.

According to a preferred embodiment of process variant a) the reaction is carried out in melt or by heating in organic solvents, preferably at a temperature of 80 to 180 ° C. As the solvent, an excess amount of the secondary amine of 2Q of the general formula (III) may also be used. Further suitable organic solvents include aromatic hydrocarbons such as benzene, toluene, chlorobenzene or dichlorobenzene. As an acid binding agent. excess amount of secondary amine or alkali metal hydroxides, carbonates or hydrogen carbonates may be used.

The compounds of general formula (I) can be isolated by known techniques such as crystallization, extraction, if desired, acid addition salts and quaternary salts can also be prepared.

The starting compounds of general formula (II) can be prepared by halogenating or acylating the corresponding 6-hydroxymethyl-1,2,4-oxadiazine derivatives. Sulfuric acid halides can be used for the acylation. [Chem. Ber. 108, 1911 (1975)].

Process variant b) according to the invention is preferably carried out in an aqueous alkali metal hydroxide solution at the boiling temperature of the reaction mixture. To increase the

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The solubility of the starting compounds of general formula (IV) may also be carried out in a mixture of aqueous solutions of alkali metal hydroxides and water miscible organic solvents such as ethanol, methanol or dioxane. Compounds of general formula (I) can be isolated by known techniques, e.g. by crystallization or extraction.

The starting compounds of general formula (IV) are novel compounds, and the present invention therefore also relates to these compounds for use as starting compounds of process variant b). They can be prepared from the novel compounds of the general formula (VI) R 4 16 r 1 - <?> »- (CH 2> n 'jj' I 'CH 2' - CH 2 - \ (VI> r 2 = 0 OH J R ", R4, R4, R ^, m and n are as defined above by halogenating agents such as thionyl chloride or phosphorus pentachloride in known manner. On the other hand, compounds of the general formula (VI) can be prepared by following the procedure described in Chem. Ber. 108, 1911 (1975), for example, by reacting compounds of the general formula (VII)

R1 - (CH) - (CH2j - C - N - Q

\ m 11 (VII) L N C = 0 r 2 \ y 30 2 wherein R, R, m, n and Q are as defined ^ having compounds of the general formula (III).

The compounds of the invention of general formula (I) or pharmaceutically acceptable acid addition salts thereof are used in admixture with nontoxic, pharmaceutical

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acceptable organic and / or inorganic carriers and optionally other additives in pharmaceutical compositions which can be prepared in various forms including solid compositions such as tablets, dragees, etc., and liquid preparations such as solutions and emulsions. The pharmaceutical compositions are prepared by techniques which. is known in the pharmaceutical industry.

The method according to the invention is illustrated in more detail in the following examples.

Example 1

To 5.0 g of 3-phenyl-6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine (Chem. Ber. 10S, 1911 (1975)) is added 37 ml of cyclohexylamine. The reaction mixture is then refluxed for 10 hours. The excess cyclohexylamine is evaporated in vacuo and to the evaporation residue is added 100 ml of ethyl acetate. The mixture is boiled and the insolubles are filtered off while the mixture is hot.

The mother liquor is evaporated in vacuo, the residue is dissolved in iso-propanol, and the solution is acidified by the addition of hydrogen chloride gas. There are obtained 4.0 g of 3-phenyl-6-cyclohexylaminomethyl-5,6-dihydro-4H-1,2,4-oxadiazine dihydrochloride, mp 240 to 244 ° C (after recrystallization from isopropanol).

Analysis for c16 H25 N3 OC12: Calculated: C = 55.49%; H = 7.28%; N = 12.14%; Cl = 20.48%.

Found: C = 55.27%; H = 8.40%; N = 12.04%; Cl = 20.25%.

LD3Q: 51 mg / kg i.v. on mice.

10 minutes after administration of a 2.5 mg / kg i.v. dose of the compound is observed a 20% decrease in blood pressure in anesthetized cats. In dogs, a 10 mg / kg i.v. dose in a 15% reduction in peripheral resistance. In dextran edema studies in rats, a 5.1 mg / kg dose provides a 15% protective effect.

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Example 2

Following the procedure described in Example 1, but starting with 3-phenyl-6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine and methyl-cyclohexylamine, 3-phenyl-65 is obtained - (N -methyl-Ni-cyclohexy- -aminomethyl-5,6-dihydro-4H-1,2,4-oxadiazine dihydrochloride, mp 243-246 ° C (after recrystallization from absolute alcohol).

Analysis for C ^ yHN ^O₂S

Calculated: C = 56.66%; H = 7.55%; N = 11.66%; Cl = 19.68%.

Found: C = 57.07%; H = 7.91%; N = 11.35%; Cl = 20.09%.

Example 3

To 2.0 g of 3-phenyl-6-tosyloxymethyl-5,6-dihydro-4H- -1,2,4-oxadiazine are added 30 ml of chlorobenzene and 3 ml of methylcyclohexylamine and the reaction mixture is refluxed for 6 hours. The mixture is then cooled and the precipitated product is filtered off, dissolved in ethyl acetate and the solution is sieved with hydrogen chloride acid in ethanol. 1.1 g of 3-phenyl-6- (N-methyl-N-cyclohexylamino) methyl-5,6-dihydro-4H-1,2,4-oxadiazine dihydrochloride having the same properties as the product of Example 2.

Example 4

To 50.6 g of 3-phenyl-4- [3- (1,2,3,4-tetrahydro-2-iso-2-quinolyl) -2-chloropropyl] -1,2,4-oxadiazolin-5-one Hydrochloride is added to 300 ml of 96% ethanol and 300 ml of a 10% sodium hydroxide solution, the reaction mixture is refluxed for 1 1/2 hour and the ethanol is evaporated in vacuo. After cooling, 33.9 g of crystalline 3-phenyl-6- (1,2,3,4-tetrahydro-2-isoquinolyl) -methyl-5,6-dihydro-4H-1,2,4-oxadiazine, m.p. 187-189 ° C after recrystallization from absolute ethanol.

30

Analysis for c19 H21 + 30:

Calculated: C = 74.24%; H = 6.89%; N = 13.67%.

Found: C = 74.50%; II = 7.06%; N = 13.59%.

The hydrochloride of the product is precipitated from a solution 35 in isopropanol by the addition of hydrogen chloride gas. The hydrochloride melts at 240 ° C.

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Analysis for C19H23N30Cl2:

Calculated: Cl = 18.65%.

Found: Cl = 18.95%.

LD5q: 332 mg / kg p.o. on mouse? 52.8 mg / kg i.v. on mice.

A 10 mg / kg dose of the compound increases blood flow in the femoral artery of dogs to 181% 2 minutes after administration. The increase obtained corresponds to 246% local conductivity (control 100%). Under the same conditions, blood pressure is reduced to 72% of its original value, minute volume 10 is increased to 125%, and coronary blood flow is increased to 127%. 4 mg / kg i.p. The dose of the compound results in a 59% increase in the amount of urine delivered in rats relative to the control. A 4 mg / kg i.v. dose shows a 35% protective effect in dextran edema experiments performed in rats.

15

Example 5

To 10.5 g of 3-phenyl-6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine are added 6.7 g of 1,2,3,4-tetrahydroisoquinoline, 6.9 g anhydrous potassium carbonate and 80 ml of chlorobenzene. The reaction mixture is refluxed for 6 hours. The solution is filtered while warm and cooled to room temperature. 6.5 g of 3-phenyl-6- (1,2,3,4-tetrahydro-2-isoquinolyl) methyl-5,6-dihydro-4H-1,2,4-oxadiazine are obtained in crystalline form. The product has the same properties as the product of Example 4. Melting point: 187 to 189 ° C.

25

Example 6

To 3.46 g of 3-phenyl-6-tosyloxymethyl-5,6-dihydro-4H-1,2,4-oxadiazine are added 1.33 g of 1,2,3,4-tetrahydroisoquinoline, 1.38 g anhydrous potassium carbonate and 30 ml of chlorobenzene.

The reaction mixture is refluxed for 2 hours, then decolorized and filtered while warm. After cooling, 1.95 g of 3-phenyl-6- (1,2,3,4-tetrahydro-2-isoquinolyl) -methyl-5,6-dihydro-4H-1,2,4-oxadiazine in crystalline form is obtained. .

The product has the same properties as the product of Example 4. Melting point: 187 to 189 ° C.

35 8 169106 o

Example 7

Following the procedure described in Example 6 but replacing chlorobenzene with 60 ml of butanol, 1.88 g of 3-phenyl-6- (1,2,3,4-tetrahydro-2-isoquinolyl) methyl-5 , 6-dihydro-4K-1,2,4-oxadiazine, having the same properties as the product of Example 4. Melting point: 187 to 189 ° C.

Example 8

Following the procedure described in Example 6, but starting with 2.7 g of 3-phenyl-6-mesyloxymethyl-5, διό-dihydro-4H-1,2,4-oxadiazine and 1,2,3,4-tetrahydro-4 isoquinoline, 1.86 g of 3-phenyl-6- (1,2,3,4-tetrahydro-2-isoquinoyl) methyl-5,6-dihydro-4H-1,2,4-oxadiazine is obtained. , having the same properties as the product of Example 4. Melting point: 187 to 189 ° C.

Examples 9-15 Following the procedure described in Example 5, but starting with 3-phenyl-6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine and 6,7-dimethoxy-1,2 3,4-tetrahydro-isoquinoline, 3-phenyl-6- (6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl) -methyl-5,6-dihydro-benzene is obtained. 4H-1,2,4-oxadiazine, m.p. 162 to 163 ° C (after recrystallization from absolute ethanol).

Analysis for

Calculated: C = 68.64%; H = 6.68%; N = 11.44%.

Found: C = 68.48%; H = 7.20%; N = 11.85%.

The product's hydrogen maleate is precipitated from a solution in absolute ethanol by maleic acid. The salt melts at 177 ° C.

Analysis for C 25 H 29 N 3 ° 7: gQ Calcd: C = 62.10%; H = 6.05%; N = 8.69%.

Found: C = 61.86%; H = 5.97%; N = 8.62%.

LD ^ q: 148 mg / kg i.v. on mice. Εώ 10 kg / mg i.v. the dose causes a sustained decrease in blood pressure in anesthetized cats.

35 9 149106

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Example 10

Following the procedure described in Example 5, but starting with 3- (2-chlorophenyl) -6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine and 1,2,3,4-tetrahydro -isoquino-5lin, 3- (2-chlorophenyl) -6- (1,2,3,4-tetrahydro-2-isoquinoly) methyl-5,6-dihydro-4H-1,2,4 is obtained -oxadiazine, mp 147 to 150 ° C after recrystallization from ethyl acetate. Analysis for C

Calculated: C = 66.76%; H = 5.90%; N = 12.29%; Cl = 10.37%.

Found: C = 66.38%; H = 5.83%; N = 12.00%; Cl = 10.69%.

The dihydrochloride of the product is precipitated by the addition of hydrogen chloride gas to an isopropanol solution thereof.

The salt melts at 227 to 230 ° C.

Analysis for C22-2343: 15: 1

Calculated: Cl = 25.65%.

Found: Cl = 25.42%.

Example 11

Following the procedure described in Example 5, but starting with 3- (4-chlorophenyl) -6-chloromethyl-5,6- -dihydro-4H-1,2,4-oxadiazine and 1,2,3,4-tetrahydro -isoquinoline, 3- (4-chlorophenyl) -6- (1,2,3,4-tetrahydro-2-isoquinolyl) -methyl-5,6-dihydro-4H-1,2,4- oxadiazine semihydrate, mp 190 to 192 ° C after recrystallization from 96% ethanol.

25

Analysis for C ]HH₂NN3OCl. 0.5 µl:

Calculated: C = 65.04%; I-I = 6.03%; N = 11.98%; Cl = 10.11%.

Found: C = 65.48%; H, 6.20%; N = 11.84%; Cl = 10.50%.

The dihydrochloride of the product is precipitated by feed 30 of. hydrogen chloride gas to an isopropanol solution thereof.

The salt melts at 249 to 252 ° C.

Analysis for C ^ HH ^N-OCOCl ^:

Calculated: Cl = 25.65%.

Found: Cl = 25.32%.

35 or 149106

Example 12

To 4.21 g of 3- (4-chlorophenyl) -4- [3- (1,2,3,4-tetra-2-hydro-2-isoquinolyl) -2-chloropropyl] -Δ. -1,2,4-oxadiazoline-5-one hydrochloride is added 30 ml of ethanol and 20 ml of 10% sodium hydroxide. The reaction mixture is then refluxed for 1 1/2 hours. The alcohol is evaporated in vacuo. 3.0 g of 3- (4-chlorophenyl) -6- (1,2,3,4-tetrahydro-2-isoquinolyl) -methyl-5,6-dihydro-4H-1,2,4-oxadiazine are obtained. -semihydrate having the same properties as the product of Example 11, Melting point: 10 190 ° C.

Example 13

To 5.94 g of 3- (4-tolyl) -6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine are added 5.32 g of 1,2,3,4-tetrahydroiso quinoline, 5.52 g of anhydrous potassium carbonate and 40 ml of absolutely 15 xylene. The reaction mixture is then refluxed for 8 hours.

The insolubles are filtered off while the mixture is hot. The filtrate is cooled to room temperature and the crystalline precipitate obtained is filtered off and dried. The product is then dissolved in isopropanol and hydrogen chloride gas is added to give 4.1 g of 3- (4-tolyl) -6- (1,2,3,4-tetrahydro-2-isoquinolyl) methyl-5, 6-dihydro-4H-1,2,4-oxadiazine dihydrochloride, m.p. 250 ° C.

Analysis for ^ 0 ^ 25 ^ 3 ° ^ ½5

Calculated: Cl = 17.98%.

Found: Cl = 18.44%.

Example 14

Following the procedure described in Example 4, but starting with 4.5 g of 3-benzyl-4- [3- (1,2,3,4-tetrahydro-2 -2-isoquinolyl) chloropropyl] - / χ -1 2,4-oxadiazolin-5-one hydrochloride, 2.4 g of 3-benzyl-6- (1,2,3,4-tetrahydro-2-isoquinolyl) methyl-5,6-dihydro is obtained. -4H-1,2,4-oxadiazine, m.p. 146 to 148 ° C after recrystallization from isopropanol.

Analysis for C20H23N3Oi

Calculated: C = 74.73%; H = 7.21%; N = 13.07%.

Found: C = 74.35%; H = 7.06%; il = 12.68%.

o 149106 11

Example 15

Following the procedure described in Example 1, but starting with 3- (2,2-diphertylethyl) -6-chloromethyl-5,6-dihydro-4H-1,2,4-oxadiazine and cyclohexylamine, 5-3 ( 2,2-diphenylethyl) -6-cyclohexylaminomethyl-5,6-dihydro-1,2,4-oxadiazine dihydrochloride, m.p. 252 to 255 ° C.

Analysis for C24H33N3OCl2:

Calculated: C = 63.99%; H = 7.38%; N = 9.33%; Cl = 15.74%.

Found: C = 64.15%; H = 7.49%; N = 9.28%; Cl = 15.66%.

LDjjq = 16.0 mg / kg i.v. on mice.

Example 16

Following the procedure described in Example 1, but starting with 3- (2,2-diphenylethyl) -6-chloromethyl-5,6-15-dihydro-4H-1,2,4-oxadiazine and methylcyclohexylamine, 3- ( 2,2-diphenylethyl-1) -6- (N-methyl-N-cyclohexyl) -aminomethyl-5,6-dihydro-4H-1,2,4-oxadiazine dihydrochloride, m.p. 227 to 230 ° C.

Analysis for C₂ ^H3gN3OCl₂: Calculated: C = 64.64%; H = 7.60%; N = 9.05%; Cl = 15.27%.

Found: C = 65.01%; H = 7.75%; N = 9.14%; Cl = 14.94%.

LD ^ g: 160.0 mg / kg i.v. on mice. At a 1 mg / kg i.v. the dose of the compound increases blood flow in the artery femoralis in dogs by 70% 5 minutes after administration.

25 The same dose reduces the blood pressure of anesthetized cats by 20%. In dextran edema experiments performed in rats, the 16 mg / kg dose of the compound provides 55% protection. Administration of a 16 mg / kg i.p. The dose in mice increases over 160 hours in urine excretion to 160% over the untreated control (100%).

Example 17

Following the procedure described in Example 4, but starting with 23.0 g of 3- (2,2-diphenylethyl) -4- [3- (1,2,2-2,4-tetrahydro-2-isoquinolyl) -2 -chloropropyl] -Δ-1,2,4-35 -oxadiazolin-5-one hydrochloride, 15.4 g of 3- (2,2-diphenylethyl) -6- (1,2,3,4-tetrahydro-hydrochloride) is obtained. 2-isoquinolylmethyl-5,6-o-dihydro-4H-1,2,4-oxadiazine, mp 163 ° C after recrystallization from absolute ethanol.

Analysis for ^ 7 ^ 29 ^ 3 ° 1

Calculated: C = 78.80%; H = 7.10%; N = 10.21%.

Found: C = 78.95%; H = 7.15%; N = 10.46%.

The dihydrochloride of the product is precipitated by the addition of hydrogen chloride gas to an isopropane solution thereof. The salt melts at 240 to 245 ° C.

Analysis for C27H31N3OCl2! Calculated: C = 66.93%; H = 6.45%; N = 8.67%; Cl = 14.64%.

Found: C = 66.54%; H = 6.05%; N = 8.37%; Cl = 14.20%.

= 72.0 mg / kg i.v. on mice. A 3.6 mg / kg i.v. the dose of the compound reduces the blood pressure of anesthetized cats by 20%.

Example 18

To 1.2 g of 3- (2,2-diphenylethyl) -6-mesyloxymethyl-5,6-dihydro-4H-1,2,4-oxadiazine are added 1.0 ml of 1,2,3,4-tetrahydro -isoquinoline and 15 ml of chlorobenzene. The reaction mixture is refluxed for 10 hours. The solvent is evaporated in vacuo and ethyl acetate is added to the residue. 0.6 g of 3- (2,2-diphenylethyl) -6- (1,2,3,4-tetrahydro-2-isoquinolyl) methyl-5,6-dihydro-4H-1,2,4 is obtained -oxadiazine having the same properties as the product of Example 17. Melting point: 163 ° C.

OC

Example 19

Following the procedure described in Example 18, but starting with 2.0 g of 3- (2,2-diphenylethyl) -6-tosyloxymethyl-5,6-dihydro-4H-1,2,4-oxadiazine, 1 is obtained. 0 g of 3- (2,2-diphenyethyl) -6- (1,2,3,4-tetrahydro-2-isoquinolyl) -30-methyl-5,6-dihydro-4H-1,2,4-oxadiazine having the same properties as the product of Example 17. Melting point: 163 ° C.

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13 149106

Preparation of the starting material of general formula (IV) via compounds of general formula (VI)

Example 2Q

To a solution of 2.18 g of 3-phenyl-4- (2,3-epoxy-propyl) -1,2,4-oxadiazolin-5-one in 50 ml of absolute ethanol is added 1, 33 g of 1,2,3,4-tetrahydroisoquinoline. The reaction mixture is refluxed for 2 hours. The solvent is evaporated and the residue is dissolved in isopropanol. The solution is acidified with hydrochloric acid in ethyl acetate. 2.47 g of 3-phenyl-4- [3- (1,2,3,4-tetrahydro-2-isoquinolyl) -2-hydroxy-2-propyl) -2 is obtained. -1,2,4-oxadiazolin-5-one hydrochloride in crystalline form, m.p. 210 to 212 ° C.

Analysis for C2Q H22C1N303:

Calculated: C = 61.93%; H = 5.72%; N = 10.83%.

Found: C = 61.62%; H = 5.50%; N = 11.06%.

Example 21

Following the procedure described in Example 20, but starting with 3- (4-chlorophenyl) -4- (3-chloro-2-hydroxy-2-propyl) -1-, 2,4-oxadiazolin-5-one and 1 , 2,3,4-tetrahydroisoquinoline, 3- (4-chlorophenyl) -4- [3- (1,2,3,4-tetrahydro-2 -2-isoquinolyl-2-hydroxypropyl) -1 1,2,4-oxadiazolin-5-one hydrochloride, mp 219 to 221 ° C, after recrystallization from isopropanol.

Analysis for c20 H21 Cl2 N3 O3: Calculated: C = 56.88%; H = 5.01%; N = 9.95%; Cl = 16.79%.

Found: C = 56.65%; H = 4.86%; N = 10.20%; Cl = 16.68%.

Example 22

Following the procedure described in Example 20, but starting with 3-benzyl-4- (3-chloro-2-hydroxypropyl) -30 2 ~ Δ -1 / 2,4-oxadiazolin-5-one and 1,2,3 , 4-tetrahydro-isoquinoline, 3-benzyl-4- [3- (1,2,3,4-tetrahydro-2-isoquinolyl) -2-2-hydroxypropyl] -1,2,4-oxadiazoline-5 is obtained. on hydrochloride, mp 194 to 197 ° C, after recrystallization from 96% ethanol.

35

Analysis for C 21 H 24 Cl 2;

Calculated: C = 62.76%; H = 6.02%; N = 10.46%; Cl = 8.82%.

Found: C = 63.18%; H = 6.13%; N = 10.18%; Cl = 8.75%.

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Example 23 40/0 g of 3-phenyl-4- [3- (1,2,3,4-tetrahydro-2-isoquinolyl) -2-hydroxypropyl] - α-1,2,4-oxadiazolin-5-one -hydrochloride is dissolved in 300 ml of chloroform and 100 ml of 5 thionyl chloride are added dropwise to the solution while boiling and stirring.

The reaction mixture is boiled for a further 1 1/2 hours, evaporated on a water bath and the residue is recrystallized from 200 ml of 96% ethanol. 27.3 g of 3-phenyl-4- [3- (1,2,3,4-2-tetrahydro-2-isoquinolyl) -2-chloropropyl] - [1,2,2,4-oxadia-10] are obtained. zolin-5-one hydrochloride, mp 210 to 212 ° C.

Analysis for C20 H21 Cl2 N3 ° 2:

Calculated: C = 59.12%; H = 5.11%; N = 10.34%; Cl = 17.54%.

Found: C = 59.20%; H = 5.19%; N = 9.99%; Cl = 17.88%.

Example 24, 15.75 g of 3-phenyl-4- [3- (1,2,3,4-tetrahydro-2-isoquinolin-2-yl) -2-hydroxypropyl] -1,2,4 oxadiazolin-5-one hydrochloride is boiled for 1 hour with 126.0 ml of phosphorus oxychloride. The solution is evaporated to dryness, to the oily residue is added 200 ml of absolute methanol under cooling, the crystalline precipitate is filtered off and finally washed with ethanol.

84.97 g of 3-phenyl-4- [3- (1,2,3,4-tetrahydro-2-iso-quinolyl) -2-chloropropyl] -1,2,4-oxadiazoline-5 are obtained. -one hydrochloride having the same properties as the product obtained in Example 23. Melting point 210 to 212 ° C.

25

Example .25 3.8. g of 3- (2-chlorophenyl) -4- [3- (1,2,3,4-tetrahydro-2-2-isoquinolyl) -2-hydroxypropyl] - <3 -1,2,4-oxadiazoline-5 -one hydrochloride and 10.0 ml of phosphorus oxychloride are boiled for 1 hour. The mixture is then evaporated and the oily rema

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recrystallize from 25 ml of isopropanol (decolorization).

2.13 g of 3- (2-chlorophenyl) -4- [3- (1,2,3,4-tetrahydro-2-2-isoquinolyl) -2-chlorophenyl] -1 oxadiazolin-5-one - hydrochloride.

Analysis for C ^H ^C CC ^:

Calculated: C = 54.50%; H + = 4.57%; N = 9.53%; Cl = 24.14%.

Found: C = 54.20%; H = 4.84%; N = 9.02%; Cl = 24.01%.

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Example 26 10.0 g of 3-benzyl-4- [3- (1,2,3,4-tetrahydro-2-isoquino-2-yl) -2-hydroxypropyl) -1,2,4-oxadiazolin-5-one Hydrochloride is boiled in a mixture of 70.0 ml of chloroform and 25.0 ml of 5 thionyl chloride for 2 hours. The mixture is evaporated and the residue is recrystallized from 96% ethanol. 5.0 g of 3-benzyl--4- [3- (1,2,3,4-tetrahydro-2-isoquinolyl) -2-chloropropyl] -2 -Δ is obtained. Ί, 2,4-oxadiazolin-5-one hydrochloride, mp 203 to 205 ° C.

Analysis for c 21 H 23 Cl 2 N 3 ° 2:

Calculated: C = 16.90%.

Found: C = 16.79%.

The content of active ingredient in the pharmaceutical compositions may vary within wide limits.

The daily dose depends on the severity of the patient's condition, on the patient's age and weight, on the formulation used and on the activity of the active ingredient, and the dose may also be varied within wide limits. The daily dose is usually 1 to 500 mg of active ingredient / kg body weight.

Claims (3)

149106 o ....... P a t e n t k r a v. 1. Analogous Process for Preparation of 1,2,4-Oxadiazine Derivatives of General Formula (X) 5 R1 - (9H) m - (CH2 »n - f2 Vo / H 'CH2 - N (I> R 5 wherein 1 2 R and R are independently phenyl which is optionally substituted 1 or 2 times with alkyl of 1-4 carbon atoms or with halogen, 4 R means hydrogen or alkyl of 1-4 carbon atoms, R5 means cycloalkyl with 5-7 carbon atoms or alkyl of 1-6 carbon atoms, 4,5 or R and R are taken together for a group of the general formula (V) 25. CH 2 VN R 6 - JQt / 30 wherein R is hydrogen or alkoxy of 1-4 carbon atoms and m and n represent 0 or 1, or pharmaceutically acceptable acid addition salts or quaternary salts thereof, characterized in that a) translates a compound of general formula (II) o 17 149106 Η R 1 - (CH) m - (CB 2) n - c / 2 CH 2 (II) R 2 'CH 2' 2 wherein R and R, m and n are as defined above and Z is halogen or sulfonyloxy, with a compound with the general formula (III) / r 4 · = HKK (1H) \ r 5 wherein R 1 and R 5 are as defined above, or b) reacting a compound of the general formula (i y). R4 R1 - (CH) m - (CH2) n - C _ H - CH2 - CH - CH2 - N (IV) i2 I Lo T 15 \ / 25 wherein R ^, R ^, R ^, R ^, m and n is as defined above and Y stands for halogen, with a base, and optionally converts an obtained compound of general formula (I) into a pharmaceutically acceptable acid addition salt or quaternary salt thereof. Analogous process according to claim 1, characterized in that the reaction in process a) is carried out in melt or in an organic solvent. Analogous process according to claim 1, characterized in that the reaction at process a) is carried out at the boiling temperature of the solvent used.